HOW DO CALCIUM-ANTAGONISTS DIFFER IN CLINICAL-PRACTICE

The majority of calcium antagonists used clinically belong to three di stinct chemical classes: the phenylalkylamines, the dihydropyridines, and the benzothiazepines. In recent years their mode of action has bee n unravelled, their limitations recognized, and their efficacy and use in the management of patients with a broad spectrum of cardiovascular and other disorders defined. It is clear, however, that these drugs a re not all alike, providing an explanation for their differing effects . The final therapeutic effect in humans depends on the mechanisms of action at the molecular level, the tissue selectivity, and the hemodyn amic changes of each agent. All these aspects are examined in detail i n this article. Concepts that are highlighted are as follows: (a) Mole cular biology has allowed recognition of the polypeptide components of the alpha 1 subunit of the L-type Ca2+ channel and the finding of pep tide segments covalently labelled by all three classes of drugs. (b) T he location of these segments within the peptides is different: Bindin g sites for dihydropyridines are located externally, whereas those for verapamil and diltiazem are located internally, in the cytosolic part of the membrane. (c) Dihydropyridine binding is voltage dependent. Th is explains the selectivity of this class of drugs for vascular smooth muscle, which is more depolarized than cardiac muscle. (d) Phenylalky lamines and benzothiazepines reach their receptors at the internal sur face of the sarcolemma through the channel lumen. Their binding is fac ilitated by the repetitive depolarization of atrioventricular and card iac tissue, a phenomenon described as use dependence. This explains wh y these drugs are not highly selective, but equipotent for the myocard ium, the atrioventricular conducting tissue, and the vasculature. (e) Dihydropyridines act through selective vasodilatation and may increase heart rate and contractility via a reflex mechanism. On the contrary, phenylalkylamines and diltiazem act through a combination of effects, including reduction of afterload, heart rate, and contractility. When taken together, all these differences distinguish the preferential cl inical utilization of one of these compounds for a given cardiovascula r pathology.